The overall goal of this proposed research is to investigate tetrahydrocannabional (THC) receptors. Our specific aims are to evaluate natural cannabinoids and their analogs for specific antagonistic activity of delta-8-THC-induced hypothermia, hypo-activity and analgesia in mice, TCH generalization in rats, and overt behavioral effects of THC in dogs. Analogs will include alkylating and non-alkylating agents. The second aim is to carry out biodispositional studies in order to localize THC binding sites centrally which will provide insight into the functionality of these receptors. The third aim is to characterize THC receptors using in vitro binding techniques. Several radiolabeled ligands, including THC, water soluble derivatives of THC and THC antagonists, will be used to study the binding sites in brain fractions. The discovery of a specific cannabinoid antagonist coupled with the in vitro characterization of a specific binding site will provide for the first time, compelling evidence for the existence of a THC receptor. Identification of such a receptor would provide insight into the mechanism responsible for THC's neuropharmacological and neurophysiological effects. These findings would lead to a search for the endogenous substrate for these receptors, the identification of which would provide a better understanding of the consequences of marihuana use.